This research program will investigate the relationship between neuron survival and intracellular Ca2+ homeostasis. We have found that both of these functions are defective in neurons from the trisomy 16 (Ts16) mouse. The Ts16 mouse has an extra copy of chromosome 16, the mouse homolog of human chromosome 21. Since patients with trisomy 21 (down syndrome) inevitable develop Alzeheimer's disease (AD), a neurodegenerative disorder characterized by neuronal death, understanding the mechanisms regulating Ts16 neuron survival may reveal abnormalities that contribute to AD. Using a novel in vitro assay for neuron survival, we have discovered that hippocampal neurons from the Ts16 mouse die 2-3 times faster than do normal (euploid) neurons. Our data demonstrate that survival of euploid neurons is promoted by micromolar concentrations of glutamate acting at kainate/AMPA receptors. Ts16 neurons lack this survival response to glutamate and this deficit can account for the accelerated death of Ts16 neurons. In contrast, both euploid and Ts16 neurons are rescued by peptide growth factors and killed by excitotoxic concentrations of added glutamate. Using computer-assisted fura-2 [Ca2+] imaging, we have also discovered that Ca2+ homeostasis is abnormal in both Ts16 neurons and astrocytes. We hypothesize that survival-promoting concentrations of glutamate maintain [Ca2+]cyt in an optimal range for euploid neuron survival and that this response is lacking in Ts16 neurons due to a genetically- determined defect in Ca2+ homeostasis. These hypotheses will be tested by correlating neuron survival with [Ca2+] in parallel experiments under conditions of varying degrees of survival. We propose experiments to determine the cellular mechanism underlying glutamate-promoted survival of normal neurons and the mechanistic basis for defective survival and Ca2+ homeostasis in Ts16 neurons. The Ts16 mouse is a naturally-occurring genetic defect that confers two discrete, but interested, deficits n normal cell physiology, viz., decreased neuronal survival and altered Ca2+ homeostasis. Both of these deficits may be masked in vivo by compensatory processes depending on cell type and cellular environment and, therefore, are most easily studied in vitro under well-controlled conditions. Deficits of this kind would be expedited to make cells vulnerable to toxic influences that accumulate with aging. Such vulnerability may play a role in the development of neurodegenerate disorders.